Investigating immunosuppressive mechanisms in primary and metastatic colorectal cancer

Despite the improvement in cancer treatment achieved through immune checkpoint blockade (ICB), durable curative responses are realised in only a minority of patients with certain cancers. This is best evidenced in colorectal cancer (CRC), where only the small subset of patients with deficient mismatch repair disease receive real benefit from ICB. A fundamental challenge for most CRC patients is the high prevalence of liver metastases. This is characteristic of late-stage disease and is strongly associated with poor response to treatment and survival. The overarching aim of this project is to better understand key suppressive mechanisms in primary and metastatic tumours, insight that is vital to support the design of better treatments combinations tailored for different CRC patients.

To interrogate the immunosuppressive mechanisms that form in CRC, we have developed sophisticated orthotopic models utilising tumour organoid implantation directly into the colon wall via colonoscopy. Slow growing primary tumours form and then naturally metastasise to the liver. Exploiting dynamic labelling approaches pioneered with the lab, mechanistic studies focus on understanding how different tumour microenvironments shape immune cell fate and function in real time. These studies are then further supported by conditional knockout mouse models and other interventions (e.g. blocking antibodies) to test effects on anti-tumour responses.

This project will provide a wealth of training opportunities and is ideal for students wishing to develop expertise in studying immune responses to cancer utilising the most advanced in vivo models available. The lab is medium-sized (~10 members), with dedicated technical support for in vivo research and a collaborative and supportive ethos.